Antineoplastic Agent, Miscellaneous

Treatment of patients with persistent or recurrent cutaneous T-cell lymphoma whose malignant cells express the CD25 component of the IL-2 receptor

C

Animal reproduction studies have not been conducted. Should be given to a pregnant mother only if clearly needed. The excretion of denileukin diftitox in breast milk is unknown, however, it is recommended that a breast-feeding woman who is treated with denileukin diftitox should discontinue nursing.

Known hypersensitivity to denileukin diftitox, diphtheria toxin, interleukin-2 or any component of the formulation

Acute hypersensitivity reactions, including anaphylaxis, may occur; most events occur during or within 24 hours of the first dose of a treatment cycle. Has been associated with a delayed-onset vascular leak syndrome, which may be severe. The onset of symptoms of vascular leak syndrome usually occurred within the first 2 weeks of infusion and may persist or worsen after cessation of denileukin diftox. Pre-existing low serum albumin levels may predict or predispose to vascular leak syndrome. Denileukin diftitox may impair immune function. Use with caution in patients with pre-existing cardiovascular disease and in patients >65 years of age.

The occurrence of adverse events diminishes after the first two treatment courses. Infusion-related hypersensitivity reactions have been reported in 69% of patients. Reactions are variable, but may include hypotension, back pain, dyspnea, vasodilation, rash, chest pain, tachycardia, dysphagia, syncope or anaphylaxis. In addition, a flu-like syndrome, beginning several hours to days following infusion, occurred in 91% of patients.

In 27% of patients a vascular leak syndrome occurred, characterized by hypotension, edema, or hypoalbuminemia. The syndrome usually developed within the first two weeks of infusion. Six percent of patients who developed this syndrome required hospitalization. The symptoms may persist or even worsen despite cessation of denileukin diftitox.

Severe (Grade 3 and 4) reactions which occurred with an incidence over 10% included: Chills/fever (22%), asthenia (22%), infection (24%), pain (13%), nausea/vomiting (14%), hypoalbuminemia (14%), transaminase elevation (15%), edema (15%), dyspnea (14%), and rash (13%).

The following list of symptoms reported during treatment includes all levels of severity:

>10%:

Cardiovascular: Edema (47%), hypotension (36%), chest pain (24%), vasodilation (22%), tachycardia (12%)

Central nervous system: Fever/chills (81%), headache (26%), pain (48%), dizziness (22%), nervousness (11%)

Dermatologic: Rash (34%), pruritus (20%)

Endocrine & metabolic: Hypoalbuminemia (83%), hypocalcemia (17%), weight decrease (14%)

Gastrointestinal: Nausea/vomiting (64%), anorexia (36%), diarrhea (29%)

Hepatic: Increased transaminases (61%)

Hematologic: Decreased lymphocyte count (34%), anemia (18%)

Miscellaneous: Hypersensitivity (69%), infection (48%), vascular leak syndrome (27%), increased sweating (10%), paresthesia (13%)

Neuromuscular and skeletal: Asthenia (66%), myalgia (17%)

Respiratory: Dyspnea (29%), increased cough (26%), pharyngitis (17%), rhinitis (13%)

1% to 10%:

Cardiovascular: Hypertension (6%), arrhythmias (6%), myocardial infarction (1%)

Central nervous system: Insomnia (9%), confusion (8%)

Endocrine & metabolic: Dehydration (9%), hypokalemia (6%), hyperthyroidism (<5%), hypothyroidism (<5%)

Gastrointestinal: Constipation (9%), dyspepsia (7%), dysphagia (6%), pancreatitis (<5%)

Genitourinary: Hematuria (10%), albuminuria (10%), pyuria (10%)

Hematologic: Thrombotic events (7%), thrombocytopenia (8%), leukopenia (6%)

Local: Injection site reaction (8%), anaphylaxis (1%)

Neuromuscular & skeletal: Arthralgia (8%)

Renal: Increased creatinine (7%), acute renal insufficiency (<5%), microscopic hematuria (<5%)

Respiratory: Lung disorder (8%)

Although there is no human experience in overdose, dose-limiting toxicities include nausea, vomiting, fever, chills and persistent asthenia. Treatment is supportive and symptom-directed. Fluid balance, as well as hepatic and renal function, should be closely monitored.

Limited information. Denileukin diftitox does not appear to have an effect on cytochrome P-450 enzymes.

Storage: Store frozen at or below -10°C; cannot be refrozen

Reconstitution: Must be brought to room temperature (25°C or 77°F) before preparing the dose. DO NOT HEAT vials. Thaw in refrigerator for not >24 hours or at room temperature for 1-2 hours. Avoid vigorous agitation. Solution may be mixed by gentle swirling.

Compatibility: DO NOT use glass syringes or containers

Denileukin diftitox is a fusion protein (a combination of amino acid sequences from diphtheria toxin and interleukin-2) which selectively delivers the cytotoxic activity of diphtheria toxin to targeted cells. It interacts with the high-affinity IL-2 receptor on the surface of malignant cells to inhibit intracellular protein synthesis, rapidly leading to cell death.

Distribution: V_d = 0.06-0.08 L/kg

Metabolism: Hepatic, via proteolytic degradation (based on animal studies)

Half-life: Distribution: 2-5 minutes; Terminal: 70-80 minutes

Adults: I.V.: A treatment cycle consists of 9 or 18 mcg/kg/day for 5 consecutive days administered every 21 days. The optimal duration of therapy has not been determined. Only 2% of patients who failed to demonstrate a response (at least a 25% decrease in tumor burden) prior to the fourth cycle responded to subsequent treatment.

For I.V. use only. Should be infused over at least 15 minutes. Should not be given as an I.V. bolus. Patients should be closely observed during the infusion for symptoms of hypersensitivity. If a patient experiences a reaction, the severity of the reaction should be evaluated, and a decision should be made to either reduce the rate or discontinue the infusion. Resuscitation equipment must be readily available. Delay therapy if serum albumin is <3 g/dL.

Prior to administration, malignant cells should be tested for expression of CD25. The patient should have a CBC, blood chemistry panel, renal and hepatic function tests as well as a serum albumin level. These tests should be repeated at weekly intervals during therapy. During the infusion, the patient should be monitored for symptoms of an acute hypersensitivity reaction. After infusion, the patient should be monitored for the development of a delayed vascular leak syndrome (usually in the first 2 weeks), including careful monitoring of weight, blood pressure, and serum albumin.

No information available to require special precautions

No effects or complications reported

Patients should be closely observed during the infusion for symptoms of hypersensitivity or capillary leak syndrome.

Injection: 150 mcg/mL (2 mL)

Formulation includes EDTA and polysorbate 20, and has a pH of 6.9-7.2